Ph-dependent controlled release pharmaceutical composition for non-opioids with resistance against the influence of ethanol

ABSTRACT

The invention relates to a pH-dependent controlled release pharmaceutical composition, comprising at least one pharmaceutical active ingredient, with the exception of opioids, wherein the core is coated at least by one coating layer, controlling the release of the pharmaceutical composition, wherein the coating layer comprises a polymer mixture of i) 40-95% by weight, based on dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer or copolymer, and ii) 5-60% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0. characterized in that the coating layer further contains 110 to 250% by weight, calculated on dry weight of the polymer mixture, of a non-porous inert lubricant and the is present in an amount of at least 60% by weight calculated on the weight of core.

FIELD OF THE INVENTION

The invention relates to a pH-dependent controlled releasepharmaceutical composition for drugs that are not opioids with decreasedsusceptibility to the influence of ethanol on the release of activecompound.

TECHNICAL BACKGROUND

US 2003/0118641 A1 describes a procedure for reducing the abusepotential of oral pharmaceutical forms which contain extractableopioids. In this procedure, resistance to active compound extraction bymeans of customary domestic solvents, such as isopropyl alcohol, vodka,white wine vinegar, hot water or peroxides, 0.01 HCl in diluted alcohol,should in particular be brought about. It is proposed to formulate theactive compound with a matrix-forming polymer and an ion exchangematerial, e.g. styrene-divinylbenzene polymers, in micronized form. Theion exchange material is crucial for the function of increasedresistance to active compound extraction. The matrix-forming polymerobviously serves as a structure-imparting agent for the pharmaceuticalcore. A long list of possible substances is specified for thematrix-forming polymers, which among many other substances alsocomprises polymethacrylates. Preferred matrix-forming agents areC₁-C₆-hydroxyalkyl-celluloses.

US 2004/0052731 A1 describes a pharmaceutical form, in particularsuitable for opioid active compounds, which should contribute to thereduction of the abuse potential as a result of improper administration.It is proposed to combine a lipophilic active compound variant with awater-insoluble additive, such as, for example, a fatty acid orcrosslinked water-soluble polysaccharides.

US 2005/0163856 A1 describes a therapeutic procedure for the treatmentof patients suffering from pain with an oxycodone-containingpharmaceutical form having reduced abuse potential as a result ofdissolution in a solvent and subsequent improper administration. To thisend, the active compound should be formulated with a matrix-formingpolymer selected from the group consisting of hydroxypropyl-cellulose,hydroxypropylmethylcellulose or hydroxyethylcellulose.

WO 2006/002884 A1 describes oral administration forms safeguardedagainst abuse, which contain a polymer, in particular a polyalkyleneoxide, having a fracture resistance of at least 500 N.

WO 2006/094083 A1 describes a pharmaceutical form having controlledvenlafaxine release characteristics. For the reduction of the abusepotential by addition of ethanol, the active compound is integrated intoa matrix of a gelling, crosslinked polymer, e.g. xanthan. Furtherhydrophobic polymers, inter alia also poly-methacrylates, can be addedas additives.

WO 2006/125483 describes the use of a polymer mixture for the productionof coated pharmaceutical formulations and pharmaceutical formulationswith mixed polymer coatings. The polymer mixtures are intended toprovide modified release profiles, tailor made for the certaintherapeutically requirements of different pharmaceutical ingredients,which cannot be achieved by using standard polymers. There is noindication about ethanol resistant pharmaceutical forms. In the examplespharmaceutical forms coated with mixtures of Eudragit® NE and Eudragit®FS at ratios from 5 to 50% by weight of Eudragit® FS are described.However no talcum is used in the examples or recommended in thedescription at high amounts as used in the present invention. Thesuitable thickness of the coatings from 2-20% by weight, based on theweight of the core, is much lower than those thicknesses required forthe present invention.

WO 1994/0022431 A1 describes an oral pharmaceutical preparationcontaining a therapeutically effective amount of morphine foradministration. It consists of at least 50 individual particles with anindividual particle size in the range of 0.7 to 1.4 mm. Each particlehas a core containing a salt of morphine coated with a barrier layer.The barrier layer contains at least one water insoluble componentselected from the group of ethyl cellulose, copolymers synthesized fromacrylic or methacrylic esters and natural waxes, and a plasticizer, forproviding drug release through the coating barrier layer which issubstantially independent of pH in the range of 1.0 to 7.0. Theresulting serum concentration of morphine obtained is at least 50% ofthe maximum serum concentration during at least 12 hours after theadministration of a single dose of said preparation.

US 2007/053698 discloses methods of sustained release administration ofopioids, including but not limited to hydromorphone and oxycodone, thatexhibit improved properties with respect to co-ingestion with aqueousalcohol.

DEFINITIONS A pH-Dependent Controlled Release Pharmaceutical Composition

A pH-dependent controlled release pharmaceutical composition means apharmaceutical composition including a pharmaceutical ingredient whichis formulated with pharmaceutically acceptable film forming polymers andoptionally with other pharmaceutically acceptable excipients, where thepharmaceutical composition shows a pH-dependent controlled release ofthe pharmaceutical ingredient.

Pharmaceutical Active Ingredients with the Exception of Opioids

The pH-dependent controlled release pharmaceutical composition comprisesa core, comprising at least one pharmaceutical active ingredient, withthe exception of opioids. Pharmaceutical compositions containing one ormore opioids (opioid agonists) are explicitly excluded from the presentinvention.

Preferred are pharmaceutical active ingredients which are usuallyformulated in controlled release dosage forms or sustained releaseforms.

A suitable pharmaceutical active ingredient is for instance metoprolol.

Medicinal substances in use can be found in reference works such as, forexample, the Rote Liste or the Merck Index.

The active components or medicinal substances employed for the purposesof the invention are intended to be used on or in the human or animalbody in order

-   1. to cure, to alleviate, to prevent or to diagnose disorders,    conditions, physical damage or pathological symptoms;-   2. to reveal the condition, the status or the functions of the body    or mental states;-   3. to replace active substances or body fluids produced by the human    or animal body;-   4. to ward off, to eliminate or to render harmless pathogens,    parasites or exogenous substances, or-   5. to influence the condition, the status or the functions of the    body or mental states.

These pharmaceutically active substances may belong to one or moreactive ingredient classes such as ACE inhibitors, adrenergics,adrenocorticosteroids, acne therapeutic agents, aldose reductaseinhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha1 antagonists, remedies for alcohol abuse, amino acids, amoebicides,anabolics, analeptics, anaesthetic additions, anaesthetics(non-inhalational), anaesthetics (local), analgesics respectivelyanalgetics (with the exception of opioids), androgens, anginatherapeutic agents, antagonists, antiallergics, antiallergics such asPDE inhibitors, antiallergics for asthma treatment, furtherantiallergics (e.g. leukotriene antagonists, antianaemics,antiandrogens, antianxiolytics, antiarthritics, antiarrhythmics,antiatheriosclerotics, antibiotics, anticholinergics, anticonvulsants,antidepressants, antidiabetics, antidiarrhoeals, antidiuretics,antidotes, antiemetics, antiepileptics, antifibrinolytics,antiepileptics, antihelmintics, antihistamines, antihypotensives,antihypertensives, antihypertensives, antihypotensives, anticoagulants,antimycotics, antiestrogens, antiestrogens (non-steroidal),antiparkinson agents, antiinflammatory agents, antiproliferative activeingredients, antiprotozoal active ingredients, antirheumatics,antischistosomicides, antispasmolytics, antithrombotics, antitussives,appetite suppressants, arteriosclerosis remedies, bacteriostatics,beta-blockers, beta-receptor blockers, bronchodilators, carbonicanhydrase inhibitors, chemotherapeutic agents, choleretics,cholinergics, cholinergic agonists, cholinesterase inhibitors, agentsfor the treatment of ulcerative colitis, cyclooxygenaze inhibitorsdiuretics, ectoparasiticides, emetics, enzymes, enzyme inhibitors,enzyme inhibitors, active ingredients to counter vomiting,fibrinolytics, fungistatics, gout remedies, glaucoma therapeutic agents,glucocorticoids, glucocorticosteroids, haemostatics, cardiac glycosides,histamine H2 antagonists, hormones and their inhibitors,immunotherapeutic agents, cardiotonics, coccidiostats, laxatives,lipid-lowering agents, gastrointestinal therapeutic agents, malariatherapeutic agents, migraine remedies, microbiocides, Crohn's disease,metastasis inhibitors, migraine remedies, mineral preparations,motility-increasing active ingredients, muscle relaxants, neuroleptics,active ingredients for treatment of estrogens, osteoporosis,otologicals, antiparkinson agents, phytopharmaceuticals, proton pumpinhibitors, prostaglandins, active ingredients for treating benignprostate hyperblasia, active ingredients for treating pruritus,psoriasis active ingredients, psychoactive drugs, free-radicalscavengers, renin antagonists, thyroid therapeutic agents, activeingredients for treating seborrhoea, active ingredients to counterseasickness, spasmolytics, alpha- and beta-sympathomimetics, plateletaggregation inhibitors, tranquilizers, ulcer therapeutic agents, furtherulcer therapeutic agents, agents for the treatment of urolithiasis,virustatics, vitamins, cytokines, active ingredients for combinationtherapy with cytostatics.

Examples of suitable active components except for opioids are forinstance acarbose, acetylsalicylic acid, abacavir, aceclofenac,aclarubicin, acyclovir, actinomycin, adalimumab, adefovir,adefovirdipivoxil, adenosylmethionine, adrenaline and adrenalinederivatives, agalsidase alpha, agalsidase beta, alemtuzumab,almotriptan, alphacept, allopurinol, almotriptan, alosetron,alprostadil, amantadine, ambroxol, amisulpride, amlodipine, amoxicillin,5 aminosalicylic acid, amitriptyline, amlodipine, amoxicillin,amprenavir, anakinra, anastrozole, androgen and androgen derivatives,apomorphine, aripiprazole, arsenic trioxide, artemether, atenolol,atorvastatin, atosiban, azathioprine, azelaic acid, barbituric acidderivatives, balsalazide, basiliximab, beclapermin, beclomethasone,bemiparin, benzodiazepines, betahistine, bexaroten, bezafibrate,bicalutamide, bimatoprost, bosentan, botulinus toxim, brimonidine,brinzolamide, budesonide, budipine, bufexamac, bumetanide, bupropion,butizine, calcitonin, calcium antagonists, calcium salts, candesartan,capecitabine, captopril, carbamazepine, carifenacin, carvedilol,caspofungin, cefaclor, cefadroxil, cefalexin cefalosporins, cefditoren,cefprozil, celecoxib, cepecitabine, cerivastatim, cetirizine,cetrorelix, cetuximab, chenodeoxycholic acid, chorionic gonadotropin,ciclosporin, cidofovir, cimetidine, ciprofloxacin, cisplatin,cladribine, clarithromycin, clavulanic acid, clindamycin, clobutinol,clonidine, clopidogrel, caffeine, colestyramine, cromoglicic acid,cotrimoxazole, coumarin and coumarin derivatives, darbepoetin,cysteamine, cysteine, cytarabine, cyclophosphamide, cyproterone,cytarabine, daclizumab, dalfopristin, danaparoid, dapiprazole,darbepoetin, defepripone, desipramine, desirudin, desloaratadine,desmopressin, desogestrel, desonide, dexibuprofen, dexketoprofen,disoproxil, diazepam and diazepam derivatives, dihydralazine, diltiazem,dimenhydrinate, dimethyl sulphoxide, dimeticon, dipivoxil, dipyridarnoi,dolasetron, domperidone, and domperidane derivatives, donepzil,dopamine, doxazosin, doxorubizin, doxylamine, diclofenac, divalproex,dronabinol, drospirenone, drotrecogin alpha, dutasteride, ebastine,econazole, efavirenz, eletripan, emidastine, emtricitabine, enalapril,encepur, entacapone, enfurvirtide, ephedrine, epinephrine, eplerenone,epoetin and epoetin derivatives, eprosartan, eptifibatide, ertapenem,esomeprazole, estrogen and estrogen derivatives, etanercept,ethenzamide, ethinestradiol, etofenamate, etofibrate, etofylline,etonogestrel, etoposide, exemestan, exetimib, famciclovir, famotidine,faropenan daloxate, felodipine, fenofibrate, fenticonazole,fexofenadine, finasteride, fluconazole, fludarabine, flunarizine,fluorouracil, fluoxetine, flurbiprofen, flupirtine, flutamide,fluvastatin, follitropin, fomivirsen, fondaparinux, formoterol,fosfomicin, frovatriptan, furosemide, fusidic acid, gadobenate,galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin,gefitinib, gemfibrozil, gentamicin, gepirone, progestogen andprogestogen derivatives, ginkgo, glatiramer, glibenclamide, glipizide,glucagon, glucitol and glucitol derivatives, glucosamine and glucosaminederivatives, glycoside antibiotics, glutathione, glycerol and glycerolderivatives, hypothalamus hormones, goserelin, grepafloxacin, gyraseinhibitors, guanethidine, gyrase inhibitors, haemin, halofantrine,haloperidol, urea derivatives as oral antidiabetics, heparin and heparinderivatives, cardiac glycosides, hyaluronic acid, hydralazine,hydrochlorothiazide and hydrochlorothiazide derivatives,hydroxyomeprazole, hydroxyzine, ibritumomab, ibuprofen, idarubicin,ifliximab, ifosfamide, iloprost, imatinib, imidapril, imiglucerase,imipramine, imiquimod, imidapril, indometacin, indoramine, infliximab,insulin, insulin glargin, interferons, irbesartan, irinotecan,isoconazole, isoprenaline, itraconazole, ivabradines, iodine and iodinederivatives, St. John's wort, potassium salts, ketoconazole, ketoprofen,ketotifen, lacidipine, lansoprazole, laronidase, latanoprost,leflunomide, lepirudin, lercanidipine, leteprinim, letrozole,levacetylmethadol, levetiracetam, levocetirizine, levodopa, licofelone,linezolide, lipinavir, lipoic acid and lipoic acid derivatives,lisinopril, lisuride, lofepramine, lodoxamide, lomefloxacin, lomustine,loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine,lutropine, magnesium salts, macrolide antibiotics, mangafodipir,maprotiline, mebendazole, mebeverine, meclozine, mefenamic acid,mefloquine, meloxicam, memantine, mepindolol, meprobamate, meropenem,mesalazine, mesuximide, metamizole, metformin, methotrexate, methyl5-amino-4-oxopentanoate, methylnaloxone, methylnaloxone,methylnaltrexones, methylphenidate, methylprednisolone, metixen,metoclopramide, metoprolol, metronidazole, mianserin, mibefradil,miconazole, mifepristone, miglitol, miglustad, minocycline, minoxidil,misoprostol, mitomycin, mizolastine, modafinil, moexipril, montelukast,moroctocog, moxifloxacin, ergot alkaloids, naloxone, naproxen,naratriptan, narcotine, natamycin, nateglinide, nebivolol, nefazodone,nelfinavir, neostigmine, neramexan, nevirapine, nicergoline,nicethamide, nifedipine, niflumic acid, nimodipine, nimorazole,nimustine, nesiritide, nisoldipine, norfloxacin, novamine sulphone,noscapine, nystatin, ofloxacin, oktotride, olanzapine, olmesartan,olsalazine, oseltamivir, omeprazole, omoconazole, ondansetron, orlistat,oseltamivir, oxaceprol, oxacillin, oxaliplatin, oxaprozin, oxcarbacepin,oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole,paracetamol, parecoxib, paroxetine, pegaspargase, peginterferon,pegfilgrastrim, penciclovir, oral penicillins, pentifylline,pentoxifylline, peptide antibiotics, perindopril, perphenazine,pethidine, plant extracts, phenazone, pheniramine, phenylbutyric acid,phenyloin, phenothiazines, phenserine, phenylbutazone, phenyloin,pimecrolimus, pimozide, pindolol, pioglitazone, piperazine, piracetam,pirenzepine, piribedil, pirlindol, piroxicam, pramipexol, pramlintide,pravastatin, prazosin, procaine, promazine, propiverine, propranolol,propionic acid derivatives, propyphenazone, prostaglandins,protionamide, proxyphylline, quetiapine, quinapril, quinaprilate,quinupristine, ramipril, ranitidine, rabeprazole, raloxifen, ranolazine,rasburicase, reboxetin, repaclinides, reproterol, reserpine,revofloxacin, ribavirin, rifampicin, riluzoles, rimexolone, risedronate,risperidone, ritonavir, rituximab, rivastimen, risatriptan, rofecoxib,ropinirol, ropivacaine, rosiglitazone, roxatidine, roxithromycin,ruscogenin, rosuvastatin, rutoside and rutoside derivatives, sabadilla,salbutamol, salicylates, salmeterol, saperconazoles, thyroid hormones,scopolamine, selegiline, sertaconazole, sertindole, sertraline,sevelamer, sibutramine, sildenafil, silicates, simvastatin, sirolimus,sitosterol, sotalol, spaglumic acid, sparfloxacin, spectinomycin,spiramycin, spirapril, spironolactone, stavudine, streptomycin,sucralfate, sulbactam, sulphonamides, sulphasalazine, sulpiride,sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrine,tacrolimus, tadalafil, taliolol, talsaclidine, tamoxifen, tasonermin,tazarotene, tegafur, tegaserod, telithromycin, telmisartan, temoporfin,temozolomide, tenatoprazole, tenecteplase, teniposide, tenofovir,tenoxicam, teriparatide, terazosin, terbinafine, terbutaline,terfenadine, teriparatide, terlipressin, tertatolol, testosterone andtestosterone derivatives, tetracyclines, tetryzoline, tezosentan,theobromine, theophylline, theophylline derivatives, thiamazole,thiotepa, thr. growth factors, tiagabine, tiapride, tibolone,ticlopidine, timolol, tinidazole, tioconazole, tioguanine, tiotropium,tioxolone, tirazetam, tiropramide, trofiban, tizanidine, tolazoline,tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine,topiramate, topotecan, torasemide, trandolapril, tranylcypromine,trapidil, trastuzumab, travoprost, trazodone, trepostinil, triamcinoloneand triamcinolone derivatives, triamterene, trifluperidol, trifluridine,trimetazidines, trimethoprim, trimipramine, tripelennamine,triprolidine, trifosfamide, tromantadine, trometamol, tropalpine,trovafloxacin, troxerutin, tulobuterol, trypsins, tyramine, tyrothricin,urapidil, ursodeoxycholic acid, theophylline ursodeoxycholic acid,valaciclovir, valdecoxib, valganciclovir, valproic acid, valsartan,vancomycin, vardenafil, vecuronium chloride, venlafaxine, verapamil,verteporfin, vidarabine, vigabatrine, viloxazine, vinblastine,vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil,vitamin D and derivatives of vitamin D, voriconazole, warfarin, xantinolnicotinate, ximelagatran, xipamide, zafirlukast, zalcitabine, zaleplon,zanamivir, zidovudine, ziprasidone, zoledronic acid, zolmitriptan,zolpidem, zoplicone, zotepine.

The active components can, if desired, also be used in the form of theirpharmaceutically acceptable salts or derivatives, and in the case ofchiral active ingredients it is possible to employ both optically activeisomers and racemates or mixtures of diastereomers. If desired, thecompositions of the invention may also comprise two or more activepharmaceutical ingredients.

pH-Dependent Controlled Release

pH-dependent controlled release of the pharmaceutical ingredient meansthat when the pharmaceutical composition is exposed in an in-vitrodissolution test to buffered USP media with different pH values of about1 pH step in the range from about pH 1 to about pH 7, the amount ofpharmaceutical ingredient which is released or dissolved in the mediumat a certain time interval differs significantly in the media withdifferent pH values.

Buffered USP media with different pH values are known to the personskilled in the art. USP media with different pH values may have pHvalues for instance of pH 1.2, pH 2.0, pH 5.8, pH 6.8 and pH 7.4. Anin-vitro dissolution test may be carried out in an USP dissolutionapparatus, for instance apparatus No. II (paddle), 37° C., dissolutionagitation 50 rpm, A certain time interval may be for instance 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 hours or even more hours.

The dissolution rate in the media with different pH values differssignificantly when tested in media with different pH values pH 1.2, 2.0,4.5, 6.8 and 7.4.

For illustration, in contrast to the pH-dependent controlled releasebehaviour of the present invention a typically pH independent controlledrelease behaviour is shown for instance in WO1994/022431A1 (s.especially p. 13, table 5).

Especially the pH release behaviour of the pharmaceutical composition ofthe present invention is pH dependent because of its gastric resistance,which means that in an USP medium of pH 1.2 there is no more than 10% ofthe pharmaceutical ingredient released within 2 hours, while at higherpH values, for instance at pH 7.4, there is significantly more than 10%of the pharmaceutical ingredient released within 2 hours. In contrastthe pH independent controlled release form of WO1994/022431A1 (s. p. 13,table 5) may show an identical release rate of 15% after 2 hours in a pH1.2 or pH 7.4 buffered medium.

Inert Non-Porous Lubricant

The coating layer may further contain 110 to 250, preferably 140-220% byweight, calculated on dry weight of the polymer mixture, of annon-porous inert lubricant.

Lubricants (sometimes also called glidants) are pharmaceuticallyacceptable substances which help in preventing agglomeration of polymersduring the coating process.

Porous lubricants like silica powders are not suitable for the purposesof the present invention. Porous structures may possibly cause capillaryeffects that promote the enhanced penetration of the coating by aqueousalcohol (ethanol) containing media respectively aqueous ethanolcontaining media.

Inert means that the lubricant does normally not chemically interactwith other substances and is not soluble or only poorly soluble in waterand/or ethanol. Not soluble or only poorly soluble means more than 10parts by weight of solvent required per 1 part by weight of solute.Furthermore inert non-porous lubricants essentially do not influence theglass transition temperature of the polymer mixture of the coating.

Lubricants like glycerol monostearate (GMS), which can not be applied insufficient amounts to the coating layer to convey resistance againstethanol containing aqueous media are per se not suitable in the sense ofthe invention. Thus glycerol monostearate (GMS) is not inert in thesense of the invention.

The non-porous inert lubricant may be a layered silica component, apigment or a stearate compound.

The inert lubricant may be Ca- or Mg-stearate. The inert lubricant maybe TiO₂.

Most preferred is the inert non-porous lubricant talc.

Ethanol Resistant Pharmaceutical Formulations

Ethanol resistant pharmaceutical formulations are formulations withrelease kinetics not significantly affected in the presence of ethanol.Ethanol resistance may be an important registration requirement in thenear future. Conventional pharmaceutical coatings, particularly onpellets, are not sufficiently resistant to alcohol. Surprisingly it wasfound that coatings combining an insoluble and soluble film formerprovide a higher resistance to alcohol.

An ethanol resistant or sometimes also called rugged formulation isdefined by comparing in-vitro release data from testing at 6.8 pH inalcohol free media and equivalent media containing 40% ethanol (detailssee attachment) and maintaining a difference in release profiles of lessthan 15% if the release in alcohol free media is less than 20% of thetotal dose and a difference of less than 30% difference, if the releaseof the total dose is between 20% and 80%.

Object and Achievement

The present invention originates from controlled release pharmaceuticalforms for oral administration. This type of pharmaceutical form isintended for more or longer-lasting release of active compound, usuallyduring intestinal passage. It is attempted to achieve by means ofappropriate formulation of the pharmaceutical form, that, after aninitial increase of the concentration of the active compound in theblood level, the blood level shall remain in the therapeutically optimalrange as long as possible. Especially too high blood levelconcentrations of the active compound, which may have toxic effects,should be avoided.

In the case of the release-delaying formulations of oral pharmaceuticalforms, the influence of the gastric juice and of the intestinal juices,in particular the ionic strength and the environmental pH, issubstantially to be taken into consideration in a manner known per se. Aproblem exists in that the ideal ratios assumed here for the release ofactive compound can be altered by the general living habits,thoughtlessness or by addictive behaviour of the patients with respectto the use of ethanol or ethanol-containing drinks. In these cases, thepharmaceutical form which is actually designed for an exclusivelyaqueous medium is additionally exposed to an ethanol containing mediumof greater or lesser strength.

On account of the dissolution of oral delayed-release pharmaceuticalforms in alcoholic drinks or simultaneous or overlapping taking thereofwith alcoholic drinks, an undesired or even critical acceleration orslowing of the release of active compound can occur. In most cases thepresence of ethanol leads to an acceleration of release of theingredient. So acceleration is the major problem, while slowing isusually less critical. An acceleration or an addition of more than 30%of the release of the pharmaceutical active ingredient absolutely to therelease in % without the presence of 40% ethanol must be consideredcritically.

Since not all patients are aware of the risk of simultaneous taking of acontrolled release pharmaceutical form and ethanol-containing drinks ordo not follow or are not able to follow appropriate warnings, advice orrecommendations, the object is to design oral delayed-releasepharmaceutical forms such that their mode of action is affected aslittle as possible by the presence of ethanol.

The purpose of the present invention is expressively not to stimulate,to promote or to make possible the taking of ethanol-containing drinkstogether with delayed-release pharmaceutical forms, but to alleviate orto avoid the possibly fatal consequences of intentional or inadvertentmisuse or abuse.

OBJECT OF THE INVENTION

Because of the not predictability of in-vivo effects, the presentinvention is based on in-vitro conditions as objectively comprehensiblebases of measurement. As a sharp test condition in-vitro conditionsaccording to USP Method 1 (basket), 100 rpm buffered at pH 6.8 (EuropeanPharmacopoeia (EP)) in a medium with and without the addition to 40%(v/v) ethanol may be chosen.

One object of the invention is solved way when the controlled releasepharmaceutical composition fulfils the following conditions:

-   -   under conditions according to USP Method 1 (basket), 100 rpm        buffered at pH 6.8 (European Pharmacopoeia) where the        pharmaceutical active ingredient is released to a degree of less        than 20% without the addition of 40% (v/v) ethanol, the        difference in the release rate with the addition of 40% (v/v)        ethanol shall not be more than plus or minus 15% of the        corresponding release value without 40% (v/v) ethanol. For        example under conditions where the pharmaceutical active        ingredient is released to a degree of 18% without the addition        of 40% (v/v) ethanol, the release rate with the addition of 40%        (v/v) ethanol shall not differ to more than plus or minus 15% of        the release value without 40% (v/v) ethanol, which means that it        may be in the range from 3 to 33%.    -   under conditions according to USP Method 1 (basket), 100 rpm        buffered at pH 6.8 (European Pharmacopoeia) where the        pharmaceutical active ingredient is released to a degree of        20-80% without the addition of 40% (v/v) ethanol, the difference        in the release rate with the addition of 40% (v/v) ethanol shall        not be more than plus or minus 30% of the corresponding release        value without 40% (v/v) ethanol. For example under conditions        where the pharmaceutical active ingredient is released to a        degree of 50% without the addition of 40% (v/v) ethanol, the        release rate with the addition of 40% (v/v) ethanol shall not        differ to more than plus or minus 30% of the release value        without 40% (v/v) ethanol, which means that it may be in the        range from 20 to 80%.

A controlled release pharmaceutical composition which fulfils thiscondition can be considered to be resistant against criticallyaccelerated release of the active compound by thoughtlessness or byaddictive behaviour of the patients with respect to the use of ethanolor ethanol-containing drinks.

This situation relates essentially to the simultaneous or subsequentconsumption of an alcoholic drink together with the taking of thecontrolled release pharmaceutical form, such that the pharmaceuticalform is exposed to a strong ethanol-containing medium in the stomach orintestine.

Measurement Methods

The measurement of the percentage amount of active compound released canbe carried out, for example, by on-line UV spectroscopy at a wavelengthsuitable for the respective active compound. The methodology is familiarto a person skilled in the art.

The release of active compound can be determined according to USP, inparticular USP 28-NF23, General Chapter <711>, Dissolution, Apparatus 2(paddle), Method <724>“Delayed Release (Enteric Coated) Articles-GeneralGeneral Drug Release Standard” correct citation needed!, Method B (100rpm, 37° C.), type I basket, with the following modification: Thepharmaceutical forms are first tested at pH 6.8 using a phosphate buffer(European Pharmacopoeia (EP)), which corresponds to an artificialintestinal medium. The measurement in the ethanol containing aqueousmedium is carried out using the appropriate amount of 30 or preferably40% ethanol (v/v) in the medium.

DETAILS OF THE INVENTION

The invention is concerned with A pH-dependent controlled releasepharmaceutical composition, comprising

-   -   a core, comprising at least one pharmaceutical active        ingredient, with the exception of opioids, wherein the core is        coated at least by one coating layer, controlling the release of        the pharmaceutical composition,    -   wherein the coating layer comprises a polymer mixture of        -   i) 40-95, preferably 50-80% by weight, based on dry weight            of the polymer mixture, of at least one water insoluble            essentially neutral vinyl polymer or copolymer, and        -   ii) 5-60, preferably 20-50% by weight, based on dry weight            of the polymer mixture, of at least one anionic polymer or            copolymer, which is insoluble in a buffered medium below pH            4.0 and soluble at least in the range from pH 7.0 to pH 8.0.        -   characterized in that    -   the coating layer further contains 110 to 250, preferably        140-220% by weight, calculated on dry weight of the polymer        mixture, of a non-porous inert lubricant and the coating is        present in an amount of at least 60% by weight calculated on the        weight of core.

The Core

In a manner known per se, active ingredient-containing cores or pelletcores form the basis for the coatings of vinyl (co)polymers. Pelletizingcan be carried out on active ingredient-free spheres (nonpareills) orcore-free pellets, pellet cores, can be produced. First, a rounded,active ingredient-containing substrate with or without a core isproduced. By means of a fluidized bed process, liquid can be applied toplacebo pellets or other suitable carrier materials, the solvent orsuspending agent being evaporated. According to the preparation process,a drying step can be added. The spraying step and subsequently dryingmay be repeated several times until the intended amount ofpharmaceutical active ingredient is fully applied.

The active ingredient is as a rule brought into an organic solvent orinto water and mixed. In order to guarantee the satisfactorysprayability of the mixture, it is usually necessary to formulate amixture with relatively low viscosity. The addition of a detergent, e.g.Tween, in concentrations of 0.1 to 20, preferably 0.5 to 10% by weight,can be advantageous for the reduction of the surface tension. Inaddition to the active ingredient, they can contain furtherpharmaceutical excipients: binders, such as cellulose and itsderivatives, polyvinylpyrrolidone (PVP), moisture retention agents,disintegration promoters, s, disintegrants, (meth)acrylates, starch andits derivatives, sugar solubilizers or others.

Appropriate application processes are known, for example, from Bauer,Lehmann, Osterwald, Rothgang “Überzogene Arzneiformen” [CoatedPharmaceutical Forms] Wissenschaftliche Verlagsgesellschaft mbHStuttgart, Chap. 7, pp. 165-196.

Details are furthermore known to the person skilled in the art fromtextbooks. See, for example:

-   Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie    [Textbook of Pharmaceutical Technology]; Verlag Chemie    Weinheim—Beerfield Beach/Fla.—Basle.-   Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische Technologie    [Pharmaceutical Technology], George Thieme Verlag Stuttgart (1991),    in particular chapters 15 and 16, pp. 626-642.-   Gennaro, A., R. (Editor), Remington's Pharmaceutical Sciences, Mack    Publishing Co., Easton Pa. (1985), Chapter 88, pp. 1567-1573.-   List, P. H. (1982): Arzneiformenlehre [Pharmaceutical Form Theory],    Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

Pellet cores can be rounded by processes such as rotor agglomeration,precipitation or spray processes, in particular ultrasonic vortex sprayprocesses, to give still uncoated cores or pellet cores of defined size,e.g. 50 to 1000 μm. This has the advantage that the entire core volumeis available for active ingredient loading. The active ingredientloading can thereby again be increased in relation to the embodimenthaving an inert core.

A process of direct compaction may be used to produce cores formintablets.

Besides the pharmaceutical active ingredient, the core may comprisefurther pharmaceutical excipients: binders such as cellulose andderivatives thereof, polyvinylpyrrolidone (PVP), humectants,disintegration promoters, s, disintegrants, starch and derivativesthereof, sugar solubilizers or others.

Coating Layer Controlling the Release of the Pharmaceutical Composition

The core is coated at least by one, preferably by one or more preferablyby only one coating layer, controlling the release of the pharmaceuticalcomposition. The coating layer conveys the effect of resistance of therelease profile against ethanol containing aqueous media. The coatinglayer, controlling the release of the pharmaceutical composition mayalso be called an outer coating layer because it surrounds the core.

The (outer) coating layer controls the release of the pharmaceuticalcomposition. The coating layer conveys the effect the resistance of therelease profile against ethanol containing aqueous media.

In case of incompatibilities between ingredients of the core andingredients of the coating an insulating sub coat may be applied betweenthe core and the (outer) coating layer.

The coating layer, controlling the release of the pharmaceuticalcomposition, may be further covered with a non-functional, preferablywater soluble top coat that has essentially no influence on the releasecharacteristics.

After preparation of the active ingredient-containing cores or pelletcores, these are provided in spray processes with the coating layer,such that coated cores or coated pellets respectively are obtained. Thecoating is prepared by means of spray application from organic solution,or preferably from aqueous dispersions. For implementation, it iscrucial here that uniform, pore-free coatings result. As a rule, thecoated pellets are additionally subsequently dried for a few minutesafter the spray application before the conditioning process is begun. Asa rule, the polymer coatings contain pharmaceutically customaryexcipients such as, for example, release agents or plasticizers.

The coating layer, controlling the release of the pharmaceuticalcomposition, is present in an amount of at least 60% by weight,calculated on the weight of core. The coating is preferably present inan amount of 60-230, preferably 80-180 more preferably 120-180% byweight, calculated on the weight of core.

The amount of the coating may correspond to an average thickness of thecoating layer in range of about 75-200, preferably in the range of100-150 μm.

Pellets

The controlled release pharmaceutical composition may preferably bepresent in the form of coated pellets with an overall average diameterfrom 100 to 2000, preferably 300 to 1000 μm.

The controlled release pharmaceutical composition according to theinvention may be present in the form of coated pellets or minitabletswith an overall average diameter in the range of from 100 to 3000 μm.

The controlled release pharmaceutical composition according to theinvention may be present in the form of coated pellets with an overallaverage diameter in the range between 100 to 700 μm.

The controlled release pharmaceutical composition according to theinvention may be present in the form of coated pellets or minitabletswith an overall average diameter in the range between 1400 to 3000 μm.

Mini Tablets

The controlled release pharmaceutical composition may preferably bepresent in the form of coated mini tablets, where the mini tablets havean average diameter from 1 to 3 mm.

Water Insoluble Essentially Neutral Vinyl Polymers or Copolymers

Water-insoluble essentially neutral vinyl polymers or copolymers areunderstood to mean those polymers or copolymers which arewater-insoluble over the entire pH range of 1 to 14 and only swellablein water.

A Vinyl polymer originates from the polymerization of monomers withvinyl groups such like (meth)acrylic monomers.

Essentially neutral is meant in the sense in that the polymers, if atall, may contain only small amounts of ionic groups. Even if smallamounts of ionic groups are present the physical-chemical behaviour ofsuch polymers is almost the same as the physical-chemical of polymerswithout any ionic groups. Essentially neutral is especially meant in thesense in that the polymers contain less than 5, less than 4, less than3, less than 2 or less than 1% by weight of monomer residues withanionic or cationic side groups. Preferably the water-insoluble neutralvinyl polymers or copolymers do not contain any cationic groups. Mostpreferably the water-insoluble essentially neutral vinyl polymers orcopolymers do not contain any ionic groups at all and thus are neutralwater-insoluble vinyl polymers (100% neutral).

Especially water insoluble (meth)acrylic polymers composed of 5 or 10%by weight of monomer residues containing cationic quaternary ammoniumgroups, e.g. of the type EUDRAGIT® RS or EUDRAGIT® RL, are not suitablefor the purposes of the present invention since the resultingpharmaceutical compositions are not sufficiently resistant against theinfluence of 40% ethanol.

In general, only one or one type of water-insoluble essentially neutralvinyl polymer or copolymer is present in the pharmaceutical composition.However, it is also possible, if appropriate, for two or morewater-insoluble polymers or copolymers or types of such polymers orcopolymers to be present alongside one another or in a mixture.

Water Insoluble Polymers of the Type of Poly Vinyl Actetate

Suitable water insoluble polymers are of the type of polyvinyl acetatepolymers or copolymers derived thereof.

Examples of water insoluble poly vinyl acetate type polymers orcopolymers are polyvinyl acetate (PVAc, Kollicoat),vinylacetate-vinylpyrrolidon-copolymer (Kollidon® VA64).

Water Insoluble (Meth)Acrylic Copolymers

Among the Water insoluble (meth)acrylic copolymers neutral oressentially neutral methacrylate copolymers are suitable for purposes ofthe present invention.

Neutral (Meth)Acrylate Copolymers (EUDRAGIT® NE Type EUDRAGIT® NM Type)

Neutral or essentially neutral methacrylate copolymers consist at leastto an extent of more than 95% by weight, in particular to an extent ofat least 98% by weight, preferably to an extent of at least 99% byweight, in particular to an extent of at least 99% by weight, morepreferably to an extent of 100% by weight, of (meth)acrylate monomerswith neutral radicals, especially C₁- to C₄-alkyl radicals.

Suitable (meth)acrylate monomers with neutral radicals are, for example,methyl methacrylate, ethyl methacrylate, butyl methacrylate, methylacrylate, ethyl acrylate, butyl acrylate. Preference is given to methylmethacrylate, ethyl acrylate and methyl acrylate.

Methacrylate monomers with anionic radicals, for example acrylic acidand/or methacrylic acid, may be present in small amounts of less than 5%by weight, preferably not more than 2% by weight, more preferably notmore than 1 or 0.05 to 1% by weight.

Suitable examples are neutral or virtually neutral (meth)acrylatecopolymers composed of 20 to 40% by weight of ethyl acrylate, 60 to 80%by weight of methyl methacrylate and 0 to less than 5% by weight,preferably 0 to 2 or 0.05 to 1% by weight of acrylic acid or methacrylicacid (EUDRAGIT® NE or Eudragit® NM type).

EUDRAGIT® NE and Eudragit® NM are copolymers composed of free-radicallypolymerized units of 30% by weight of ethyl acrylate and 70% by weightof methyl methacrylate.

Preference is given to neutral or essentially neutral methyl acrylatecopolymers which, according to WO 01/68767, have been prepared asdispersions using 1-10% by weight of a nonionic emulsifier having an HLBvalue of 15.2 to 17.3. The latter offer the advantage that there is nophase separation with formation of crystal structures by the emulsifier(Eudragit® NM type).

According to EP 1 571 164 A2, corresponding, virtually neutral(meth)acrylate copolymers with small proportions of 0.05 to 1% by weightof mono olefinically unsaturated C₃-C₈-carboxylic acids can, however,also be prepared by emulsion polymerization in the presence ofcomparatively small amounts of anionic emulsifiers, for example 0.001 to1% by weight.

A suitable water insoluble polymer is a copolymer composed offree-radical polymerized units of more than 95 up to 100% by weight C₁-to C₄-alkyl esters of acrylic or of methacrylic acid and less than 5% byweight of acrylic or methacrylic acid.

Water Soluble Anionic Polymers

A water soluble anionic polymer in the sense of the present invention isa polymer which is insoluble below pH 5.0 and soluble at least in therange from pH 7.0 to pH 8.0, preferably in the range from pH 6.0 to 8.0,most preferably soluble in the range from 5.5 to 8.0 in a suitablebuffered medium, preferably a buffered medium according to USP orEuropean Pharmacopoeia standards. Most of the polymers which are solublein the range from pH 7.0 to pH 8.0 in a suitable buffered aqueous mediumare not soluble in pure water or demineralised water.

Water Soluble Anionic Cellulose Derivatives

Anionic cellulose derivates are based on a natural cellulose chain andchemically modified with anionic compounds. The polymer may by partiallyor totally neutralized, preferably with alkali ions. Examples of anioniccellulose derivatives are cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxy methyl cellulose(CMC), hydroxylpropyl methyl cellulose acetate succinate (HPMCAS) orcellulose acetate succinate (CAS).

Water Soluble Anionic (Meth)Acrylate Copolymers

A suitable water soluble anionic (meth)acrylate copolymer is composed offree-radical polymerized units of 25 to 95, preferably 40 to 95, inparticular 60 to 40, % by weight free-radical polymerized C₁- toC₄-alkyl esters of acrylic or of methacrylic acid and 75 to 5,preferably 60 to 5, in particular 40 to 60, % by weight (meth)acrylatemonomers having an anionic group.

The proportions mentioned normally add up to 100% by weight. However itis also possible in addition, without this leading to an impairment oralteration of the essential properties of the invention, for smallamounts in the region of up to 10 or 0 to 10, for example 1 to 5, % byweight of further monomers capable of vinylic copolymerization, such as,for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, to bepresent. However, it is preferred that no further monomers capable ofvinylic copolymerization are present. It is generally preferred that nofurther monomers except from those explicitly mentioned are present inthe water soluble anionic (meth)acrylate copolymers.

C₁- to C₄-alkyl esters of acrylic or methacrylic acid are in particularmethyl methacrylate, ethyl methacrylate, butyl methacrylate, methylacrylate, ethyl acrylate and butyl acrylate.

A (meth)acrylate monomer having an anionic group is, for example,acrylic acid, with preference for methacrylic acid.

Suitable anionic (meth)acrylate copolymers are those composed of 40 to60% by weight methacrylic acid and 60 to 40% by weight methylmethacrylate or 60 to 40% by weight ethyl acrylate (EUDRAGIT® L orEUDRAGIT® L 100-55 types).

EUDRAGIT® L is a copolymer of 50% by weight methyl methacrylate and 50%by weight methacrylic acid. The pH of the start of the specific activeingredient release in intestinal juice or simulated intestinal fluid canbe stated to be pH 6.0.

EUDRAGIT® L 100-55 is a copolymer of 50% by weight ethyl acrylate and50% by weight methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersioncomprising 30% by weight EUDRAGIT® L 100-55. The pH of the start of thespecific active ingredient release in intestinal juice or simulatedintestinal fluid can be stated to be pH 5.5.

Likewise suitable are anionic (meth)acrylate copolymers composed of 20to 40% by weight methacrylic acid and 80 to 60% by weight methylmethacrylate (EUDRAGIT® S type). The pH of the start of the specificactive ingredient release in intestinal juice or simulated intestinalfluid can be stated to be pH 7.0.

Suitable (meth)acrylate copolymers are those consisting of 10 to 30% byweight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to15% by weight methacrylic acid (EUDRAGIT® FS type). The pH at the startof the specific active ingredient release in intestinal juice orsimulated intestinal fluid can be stated to be pH 7.0.

EUDRAGIT® FS is a copolymer polymerized out of 25% by weight methylmeth-acrylate, 65% by weight methyl acrylate and 10% by weightmethacrylic acid. EUDRAGIT® FS 30 D is a dispersion comprising 30% byweight EUDRAGIT® FS.

Additionally suitable is a copolymer composed of

-   -   20 to 34% by weight methacrylic acid and/or acrylic acid,    -   20 to 69% by weight methyl acrylate and    -   0 to 40% by weight ethyl acrylate and/or where appropriate    -   0 to 10% by weight further monomers capable of vinylic        copolymerization,        with the proviso that the glass transition temperature of the        copolymer according to ISO 11357-2, subsection 3.3.3, is not        more than 60° C. This (meth)acrylate copolymer is particularly        suitable, because of its good elongation at break properties,        for compressing pellets to tablets.

Additionally suitable is a copolymer composed of

-   -   20 to 33% by weight methacrylic acid and/or acrylic acid,    -   5 to 30% by weight methyl acrylate and    -   20 to 40% by weight ethyl acrylate and    -   more than 10 to 30% by weight butyl methacrylate and where        appropriate    -   0 to 10% by weight further monomers capable of vinylic        copolymerization,    -   where the proportions of the monomers add up to 100% by weight,        with the proviso that the glass transition temperature of the        copolymer according to ISO 11357-2, subsection 3.3.3 (midpoint        temperature T_(mg)), is 55 to 70° C. Copolymers of this type are        particularly suitable, because of its good mechanical        properties, for compressing pellets to tablets.

The abovementioned copolymer is composed in particular of free-radicalpolymerized units of

-   -   20 to 33, preferably 25 to 32, particularly preferably 28 to 31%        by weight methacrylic acid or acrylic acid, with preference for        methacrylic acid,    -   5 to 30, preferably 10 to 28, particularly preferably 15 to 25%        by weight methyl acrylate,    -   20 to 40, preferably 25 to 35, particularly preferably 18 to 22%        by weight ethyl acrylate, and    -   more than 10 to 30, preferably 15 to 25, particularly preferably        18 to 22% by weight butyl methacrylate,        where the monomer composition is chosen, so that the glass        transition temperature of the copolymer is from 55 to 70° C.,        preferably 59 to 66, particularly preferably 60 to 65° C.

Glass transition temperature means in this connection in particular themidpoint temperature T_(mg) according to ISO 11357-2, subsection 3.3.3.Measurement takes place without added plasticizer, with residual monomercontents (REMO) of less than 100 ppm, with a heating rate of 10° C./minand under a nitrogen atmosphere.

The copolymer preferably consists essentially to exclusively of 90, 95or 99 to 100% by weight of the monomers methacrylic acid, methylacrylate, ethyl acrylate and butyl methacrylate in the ranges of amountsindicated above.

However, it is possible, without this necessarily leading to animpairment of the essential properties, for small amounts in the rangefrom 0 to 10, e.g. 1 to 5% by weight of further monomers capable ofvinylic copolymerization additionally to be present, such as, forexample, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate,vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinylacetate and/or derivatives thereof.

Preparation of Anionic (Meth)Acrylate Copolymers

The anionic (meth)acrylate copolymers can be prepared in a manner knownper se by free-radical polymerization of the monomers (see, for example,EP 0 704 207 A2 and EP 0 704 208 A2). The copolymer according to theinvention can be prepared in a manner known per se by free-radicalemulsion polymerization in aqueous phase in the presence of, preferably,anionic emulsifiers, for example by the process described in DE-C 2 135073.

The copolymer can be prepared by conventional processes of free-radicalpolymerization continuously or discontinuously (batch processes) in thepresence of free-radical forming initiators and, where appropriate,regulators to adjust the molecular weight undiluted, in solution, bybead polymerization or in emulsion. The average molecular weight Mw(weight average, determined for example by measuring the solutionviscosity) may be for example in the range from 80 000 to 1 000 000(g/mol). Emulsion polymerization in aqueous phase in the presence ofwater-soluble initiators and (preferably anionic) emulsifiers ispreferred.

In the case of bulk polymerization, the copolymer can be obtained insolid form by crushing, extrusion, granulation or hot cut.

The (meth)acrylate copolymers are obtained in a manner known per se byfree-radical bulk, solution, bead or emulsion polymerization. They mustbe brought before processing to the particle size range of the inventionby suitable grinding, drying or spraying processes. This can take placeby simple crushing of extruded and cooled pellets or hot cut.

The use of powders may be advantageous especially on mixture with otherpowders or liquids. Suitable apparatuses for producing powders arefamiliar to the skilled person, e.g. air jet mills, pinned disc mills,compartment mills. It is possible where appropriate to includeappropriate sieving steps. A suitable mill for industrial largequantities is, for example, an opposed jet mill (Multi No. 4200)operated with a gauge pressure of about 6 bar.

Partial Neutralization

The anionic polymers may be partially or fully neutralized by bases.Bases suitable are those expressly mentioned in EP 0 088 951 A2 or WO2004/096185 or derivable there from. In particular: sodium hydroxidesolution, potassium hydroxide solution (KOH), ammonium hydroxide ororganic bases such as, for example, triethanolamine, sodium carbonate,potassium carbonate, sodium bicarbonate, trisodium phosphate, trisodiumcitrate or ammonia or physiologically tolerated amines such astriethanolamine or tris(hydroxymethyl)aminomethane. Further suitablecationic, organic bases are basic amino acids histidine, arginine and/orlysine.

Multiparticulate Pharmaceutical Forms

The controlled release pharmaceutical composition according to theinvention may have the form of pellets, which are contained in amultiparticulate pharmaceutical form, for instance in the form of acompressed tablet, capsules, sachets, effervescent tablets orreconstitutable powders.

Top Coat and Sub Coats

The controlled release pharmaceutical composition according to theinvention may be further coated with a sub coat and/or a top coat.

A sub coat may be located between the core and the coating layercontrolling the release of the pharmaceutical active substance(controlling layer). A sub coat may have the function to separatesubstances of the core from substances of the controlling layer whichmay be incompatible with each other. The sub coat has essentially noinfluence on the release characteristics. A sub coat is preferablyessentially water-soluble, for instance it may consist of substanceslike hydroxyl propyl methyl cellulose (HPMC) as a film former. Theaverage thickness of the sub coat layer is very thin, for example notmore than 15 μm, preferably not more than 10 μm.

A top coat is also preferably essentially water soluble. A top coat mayhave the function of colouring the pharmaceutical form or protectingfrom environmental influences for instance from moisture during storage.The top coat may consist out of a binder, for instance a water solublepolymer like a polysaccharide or HPMC, or a sugar compound likesaccharose. The top coat may further contain pharmaceutical excipientslike pigments or lubricants in small amounts. The topcoat hasessentially no influence on the release characteristics.

The expressions sub coat and top coat is well known to the personskilled in the art.

Process for Producing a Pharmaceutical Form According to the Invention

The controlled release pharmaceutical composition according to theinvention may be produced in a manner known per se by pharmaceuticallycustomary processes such as direct compression, compression of dry, wetor sintered granules and subsequent rounding off, wet or dry granulationor direct pelleting or by binding powders (powder layering) onto activeingredient-free beads or neutral cores (nonpareilles) or activeingredient-containing particles and by applying the polymer coating in aspray process or by fluidized bed granulation.

Excipients/Customary Additives

The core may further contain, beside the pharmaceutical activeingredient, excipients or customary additives respectively in a mannerknown to the person skilled in the art.

The coating layer may also, beside the polymer mixture and thenon-porous inert lubricant as essential ingredients, further containexcipients or customary additives respectively in a manner known to theperson skilled in the art.

Excipients or customary additives respectively shall be added only atamounts which do not negatively influence the function of the core andthe out coating layer according to the invention as disclosed in here.As a guide line excipients or customary additives may be for instanceused in a way similar or identical as in the working examples disclosedin here.

Excipients customary in pharmacy, occasionally also referred to ascustomary additives, are added to the formulation of the invention,preferably during production of the granules or powders. It is, ofcourse, always necessary for all the excipients or customary additivesemployed to be toxicologically acceptable and usable in particular inmedicaments without a risk for patients.

The amounts employed and the use of excipients customary in pharmacy formedicament coatings or layerings are familiar to the skilled worker.Examples of possible excipients or additives customary in pharmacy arerelease agents, pigments, stabilizers, antioxidants, pore formers,penetration promoters, gloss agents, aromatizing substances orflavourings. They serve as processing aids and are intended to ensure areliable and reproducible production process and good long-term storagestability or they achieve additional advantageous properties in thepharmaceutical form. They are added to the polymer preparations beforeprocessing and may influence the permeability of the coatings, it beingpossible to utilize this where appropriate as additional controlparameter.

Pigments:

If pigments are additionally present they are preferably added to thetop coat. Pigments incompatible with the coating agent are in particularthose pigments which, may be added directly to a dispersion, e.g. bystirring in, in the usual amounts used of, for example, 20 to 400% byweight based on the dry weight of the (meth)acrylate copolymer, lead todestabilization of the dispersion, coagulation, to signs ofinhomogeneity or similarly unwanted effects. The pigments to be used aremoreover of course non-toxic and suitable for pharmaceutical purposes.Concerning this, see also, for example: Deutsche Forschungsgemeinschaft,Farbstoffe für Lebensmittel, Harald, Boldt Verlag K G, Boppard (1978);Deutsche Lebensmittelrundschau 74, No. 4, p. 156 (1978);Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980.

Pigments incompatible with the coating agent may be for example aluminapigments. Examples of incompatible pigments are orange yellow, cochinealred lake, coloured pigments based on alumina or azo dyes, sulphonic aciddyes, orange yellow S (E110, C.I. 15985, FD&C Yellow 6), indigo carmine(E132, C.I. 73015, FD&C Blue 2), tartrazine (E 102, C.I. 19140, FD&CYellow 5), Ponceau 4R (E 125, C.I. 16255, FD&C Cochineal Red A),quinoline yellow (E 104, C.I. 47005, FD&C Yellow 10), erythrosine (E127,C.I. 45430, FD&C Red 3), azorubine (E 122, C.I. 14720, FD&C Carmoisine),amaranth (E 123, C.I. 16185, FD&C Red 2), acid brilliant green (E 142,C.I. 44090, FD&C Green S).

The E numbers indicated for the pigments relate to an EU numbering.Concerning this, see also “Deutsche Forschungsgemeinschaft, Farbstoffefür Lebensmittel, Harald Boldt Verlag K G, Boppard (1978); DeutscheLebensmittelrundschau 74, No. 4, p. 156 (1978);Arzneimittelfarbstoffverordnung AmFarbV of 25.08.1980. The FD&C numbersrelate to the approval in food, drugs and cosmetics by the U.S. food anddrug administration (FDA) described in: U.S. Food and DrugAdministration, Center for Food Safety and Applied Nutrition, Office ofCosmetics and Colors: Code of Federal Regulations—Title 21 ColorAdditive Regulations Part 82, Listing of Certified Provisionally ListedColors and Specifications (CFR 21 Part 82).

Plasticizers

Further additives may also be plasticizers. Plasticizers may befavourably added to the coating layer. The usual amounts are between 0and 50, preferably 5 to 20, % by weight based for example on the(meth)acrylate copolymer of the layer coating layer.

Plasticizers may influence the functionality of the polymer layer,depending on the type (lipophilic or hydrophilic) and added amount.Plasticizers achieve through physical interaction with the polymers areduction in the glass transition temperature and promote filmformation, depending on the added amount. Suitable substances usuallyhave a molecular weight of between 100 and 20 000 and comprise one ormore hydrophilic groups in the molecule, e.g. hydroxyl, ester or aminogroups.

Examples of suitable plasticizers are alkyl citrates, glycerol esters,alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters,diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to 12000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethylcitrate (ATEC) and dibutyl sebacate (DBS). Mention should additionallybe made of esters which are usually liquid at room temperature, such ascitrates, phthalates, sebacates or castor oil. Esters of citric acid andsebacinic acid are preferably used.

Addition of the plasticizers to the formulation can be carried out in aknown manner, directly, in aqueous solution or after thermalpre-treatment of the mixture. It is also possible to employ mixtures ofplasticizers.

Use

The pH-dependent controlled release pharmaceutical composition accordingto the invention may be used to reduce the risk of enhanced release ofthe included pharmaceutical active ingredient after oral ingestion bysimultaneous or subsequent consumption of ethanol containing drinks(misuse).

EXAMPLES Model Drug

Studies were conducted using Metoprolol succinate as a model drug.

Micronised talc was used as an excipient.

Dissolution Studies

Coated pellets were tested according to

USP 28-NF23, General Chapter <711>, Dissolution,

Dissolution Parameters: Apparatus: USP Type-I (Basket) RPM: 100/min.Temperature: 37.5±0.5° C.

Dissolution volume: 900 ml.Withdrawal volume: 10 ml withdrawn manually using pipette, withoutreplenishment of the medium.Withdrawal interval: 1.0 Hr, 2.0 Hr, 3.0 Hr, 4.0 Hr, 5.0 Hr, 6.0 Hr, 7.0Hr, 8.0 Hr, 9.0 Hr, 10.0 Hr, 11.0 Hr and 12.0 Hr.Mode of detection: UV spectrophotometer at 274.5 nm.

Dissolution Medium 1:

Phosphate buffered saline pH 6.8 (European Pharmacopoeia=EP)

Dissolution Medium 2:

Phosphate buffered saline pH 6.8, EP with 30% v/v alcohol 0.9 g ofKH₂PO₄, 1.8 g of K₂HPO₄, 7.65 g of NaCl with 630 ml D.M. water and 270ml of alcohol.

Dissolution Medium 3:

Phosphate buffered saline pH 6.8, EP with 40% v/v alcohol-0.9 g ofKH₂PO₄, 1.8 g of K₂HPO₄, 7.65 g of NaCl with 540 ml D.M. water and 360ml of alcohol.

Copolymers

EUDRAGIT® NE is a copolymer composed of free-radically polymerized unitsof 30% by weight of ethyl acrylate and 70% by weight of methylmethacrylate.

EUDRAGIT® FS is a copolymer composed of free-radically polymerized unitsof 25% by weight methyl methacrylate, 65% by weight methyl acrylate and10% by weight methacrylic acid.

EUDRAGIT® L 100-55 is a copolymer composed of free-radically polymerizedunits of 50% by weight ethyl acrylate and 50% by weight methacrylicacid.

Formulation Details Cores:

500 g Non pareil seeds (600 microns) were loaded with 942 g Metoprololsuccinate in a conventional coating pan using an aqueous polyvinylpyrrolidone solution as a binder.

Coating Suspension Preparation:

EUDRAGIT® Dispersions are filled into or mixed in a suitable vesselapplying gentle stirring. Lubricants and different polymers aredissolved or dispersed in water applying high shear forces.

The lubricant suspension is poured into the EUDRAGIT® dispersionapplying gentle stirring. Stirring is continued through the entirecoating process.

Coating Process:

500 g drug layered pellets were coated with different coatingsuspensions in a fluidized bed apparatus under appropriate conditions,i.e. a spray rate of approximately 20 g/min coating suspension per kgcores and a bed temperature of approximately 25-30° C. Post coating thepellets was dried at 40° C. on trays for at least 2 hours in an oven.

Example 1 Comparative Example EUDRAGIT® NE 30 D/Lubricant: Talc (200%w/w of the Polymer)/90% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 500 150 Soluble polymer — — — Lubricant Talc 300 300 Diluent Water,purified 2200 —

Procedure:

500 g Metoprolol succinate pellets were coated with EUDRAGIT® NE 30 D at30% w/w level with 200% w/w talc as a lubricant in the coatingsuspension. The coating was applied in fluid bed processor using normalprocess parameters.

Dissolution Results (Example 1):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

Drug Release in % Time in with 30% (hours) without EtOH (v/v) EtOH 0 0.00.0 1 0.2 5.4 2 1.8 12.2 3 3.6 28.0 4 6.3 36.4 5 11.2 46.0 6 20.3 54.2 730.9 62.9 8 41.5 75.5 9 51.2 76.0 10 62.3 79.9 11 68.0 82.7 12 74.7 87.9

Inference:

The coated pellets failed to show resistance at even 30% v/v level ofalcohol and are therefore not expected to be resistant against 40%ethanol hence no inventive polymer combination was applied.

Example 2 Comparative Example EUDRAGIT® NE 30D/Hydroxypropyl MethylCellulose (95:5)/Lubricant: Talc (200% w/w of the Polymer)/165% w/wCoating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 870 261 Soluble polymer HPMC, 5 cps 14 14 Lubricant Talc 550 550Diluent Water, purified 4066 —

Procedure:

Metoprolol succinate pellets were coated with hydroxypropyl methylcellulose (HPMC), 5 cps in combination with EUDRAGIT® NE 30D. The ratioof EUDRAGIT® NE 30D to hydroxypropyl methyl cellulose was 9.5:0.5 with200% w/w talc as a lubricant. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 2):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

Time in % Drug Release Hr. without EtOH with 30% (v/v) EtOH 0.00 0.000.00 1.00 1.25 7.65 2.00 3.12 8.50 3.00 3.61 14.57 4.00 4.52 24.57 5.008.79 30.14 6.00 20.30 44.95 7.00 25.51 55.91 8.00 35.61 66.47 9.00 44.0773.13 10.00 52.31 78.12 11.00 60.55 83.33 12.00 67.99 86.77

Inference:

The coated pellets failed to show resistance at even 30% v/v level ofalcohol and are therefore not expected to be resistant against 40%ethanol hence no inventive polymer combination was applied.

Example 3 Comparative Example EUDRAGIT® NE 30D/EUDRAGIT® FS 30D,1:9/Lubricant: Talc (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 92 27.5 Soluble polymer EUDRAGIT ® FS 30D 825 247.5 Lubricant Talc550 550 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio 1:9 using 200% w/w talc as alubricant in coating suspension. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 3):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

% Drug Release Time in without with 30% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 2.03 4.00 2.00 1.75 55.21 3.00 3.46 87.41 4.00 22.86 97.825.00 50.78 99.89 6.00 72.83 100.00 7.00 84.90 8.00 92.89 9.00 96.2710.00 97.40 11.00 99.20 12.00 100.00

Inference:

The coated pellets failed to show resistance at even 30% v/v level ofalcohol and are therefore not expected to be resistant against 40%ethanol hence no inventive polymer combination was applied.

Example 4 Comparative Example EUDRAGIT® NE 30D/EUDRAGIT® FS 30D,7:3/Lubricant: Talc (100% w/w of the Polymer)/110% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 642 192.5 Soluble polymer EUDRAGIT ® FS 30D 275 82.5 Lubricant Talc275 275 Diluent Water, purified 2475 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio 7:3 using 100% w/w of talc as alubricant in coating suspension. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 4):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 0.95 1.67 2.00 7.75 23.23 3.00 19.41 52.53 4.00 30.07 71.585.00 42.02 85.54 6.00 53.28 93.70 7.00 65.40 96.66 8.00 70.63 98.88 9.0076.29 100.00 10.00 80.84 11.00 84.22 12.00 86.92

Inference:

The coated pellets failed to show resistance in 40% v/v level of alcoholhence the level of the non-porous inert lubricant was too low.

Example 5 Comparative Example EUDRAGIT® NE 30D/EUDRAGIT® FS 30D,7:3/Lubricant: Glyceryl Monostearate (GMS) (50% w/w of the Polymer)/94%w/w Coating/Core

Formulation details of 94% w/w coating suspension for 500 g of cores

Quantity Solids Function Ingredients in g in g Insoluble polymerEUDRAGIT ® NE 30D 642 192.5 Soluble polymer EUDRAGIT ® FS 30D 275 82.5Lubricant GMS 138 138 Emulsifier Tween 80 5.5 5.5 Diluent Water,purified 2007 —

Procedure:

Metoprolol succinate pellets were supposed to be coated with a mixtureof EUDRAGIT® NE 30D and EUDRAGIT® FS 30D at a ratio 7:3 using 50% w/w ofGlyceryl monostearate as a lubricant in coating suspension. The coatingwas intended to be applied in fluid bed processor using normal processparameters.

Note:

Coating of drug loaded pellets using combination of EUDRAGIT® NE 30D andEUDRAGIT® FS 30D with 50% w/w GMS as a lubricant in a coating suspensionwas not practically feasible because of nozzle blocking.

Example 6 Inventive EUDRAGIT® NE 30D/EUDRAGIT® FS 30D, 6:4/Lubricant:Talc (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of 165% w/w coating suspension for 500 g of coresSolids Function Ingredients Quantity in g in g Insoluble polymerEUDRAGIT ® NE 30D 550 165 Soluble polymer EUDRAGIT ® FS 30D 367 110Lubricant Talc 550 550 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio of 6:4 using 200% w/w talc as alubricant in coating suspension. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 6):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

Time in % Drug Release Hr. without EtOH with 30% (v/v) EtOH 0.00 0.000.00 1.00 8.31 4.77 2.00 19.13 22.52 3.00 38.55 49.35 4.00 57.87 72.385.00 72.81 86.91 6.00 83.15 95.19 7.00 90.12 99.21 8.00 94.06 101.149.00 97.10 10.00 98.44 11.00 99.88 12.00 100.04

Inference:

Values of the release profiles of the coated pellets tested in 30% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Dissolution Results (Example 6):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

Time in % Drug Release Hr. without EtOH with 40% (v/v) EtOH 0.00 0.000.00 1.00 8.31 6.96 2.00 19.13 34.01 3.00 38.55 66.55 4.00 57.87 87.075.00 72.81 99.95 6.00 83.15 100.00 7.00 90.12 8.00 94.06 9.00 97.1010.00 98.44 11.00 99.88 12.00 100.04

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Example 7 Inventive EUDRAGIT® NE 30D/EUDRAGIT® FS 30D, 7:3/Lubricant:Talc (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 642 192.5 Soluble polymer EUDRAGIT ® FS 30D 275 82.5 Lubricant Talc550 550 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio 7:3 using 200% w/w talc as alubricant in coating suspension. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 7):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

% Drug Release Time in without with 30% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 2.36 1.94 2.00 16.63 9.39 3.00 33.61 19.48 4.00 49.98 32.385.00 64.33 45.29 6.00 73.41 57.75 7.00 82.34 66.10 8.00 87.66 73.87 9.0095.45 82.94 10.00 98.29 87.41 11.00 100.10 91.23 12.00 101.08 94.08

Inference:

Values of the release profiles of the coated pellets tested in 30% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 3.36 2.18 2.00 16.63 13.88 3.00 33.61 31.25 4.00 49.98 50.225.00 64.33 66.90 6.00 73.41 77.03 7.00 82.34 84.73 8.00 87.66 89.35 9.0095.45 92.39 10.00 98.29 92.84 11.00 100.10 94.06 12.00 101.08 95.66

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Dissolution Studies to Show pH Dependency

The pH dependency of alcohol resistance formulation and their resistancein alcoholic dissolution medium with different pH shall be demonstrated.

(1) The formulation in Example 7 was analysed in 0.1 N HCl, USP (pH=1.2)for 2 hours and its corresponding alcoholic medium with 40% v/v ofalcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 0.25 0.00 0.00 0.50 0.00 0.01 0.75 0.03 0.21 1.00 0.03 0.41 1.500.04 2.45 2.00 0.04 4.21

Inference:

-   -   Coated pellets prove to be pH dependent.    -   Values of the release profiles of the coated pellets tested in        40% v/v hydro-alcoholic dissolution medium were resistant when        compared with the release profiles of the coated pellets tested        in dissolution medium without alcohol for all time points.

(2) The formulation in Example 7 was analysed in 0.01 N HCl, USP(pH=2.0) for 2 hours and its corresponding alcoholic medium with 40% v/vof alcohol.

% Drug Release Time in Without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 0.25 0.00 0.00 0.50 0.00 0.00 0.75 0.00 0.00 1.00 0.00 0.00 1.500.02 1.21 2.00 0.05 2.51

Inference:

-   -   Coated pellets prove to be pH dependent.    -   Values of the release profiles of the coated pellets tested in        40% v/v hydro-alcoholic dissolution medium were resistant when        compared with the release profiles of the coated pellets tested        in dissolution medium without alcohol for all time points.

(3) The formulation in Example 7 was analysed in pH 4.5, USP dissolutionmedium for 2 hours and its corresponding alcoholic medium with 40% v/vof alcohol.

% Drug Release Time in Without With 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 0.25 0.00 0.00 0.50 0.00 0.00 0.75 0.00 0.00 1.00 0.00 0.00 1.500.00 6.58 2.00 0.00 13.11

Inference:

-   -   Coated pellets prove to be pH dependent.    -   Values of the release profiles of the coated pellets tested in        40% v/v hydro-alcoholic dissolution medium were resistant when        compared with the release profiles of the coated pellets tested        in dissolution medium without alcohol for all time points.

(4) The formulation in Example 7 was analysed in pH 6.8, USP dissolutionmedium for 12 hours and its corresponding alcoholic medium with 40% v/vof alcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 0.00 1.06 2.00 6.61 16.42 3.00 25.04 33.73 4.00 41.46 53.315.00 56.62 78.29 6.00 68.62 82.46 7.00 77.22 88.01 8.00 83.06 92.82 9.0085.65 96.54 10.00 88.32 99.54 11.00 90.36 100.00 12.00 91.91 100.00

Inference:

-   -   Coated pellets prove to be pH dependent.    -   Values of the release profiles of the coated pellets tested in        40% v/v hydro-alcoholic dissolution medium were resistant when        compared with the release profiles of the coated pellets tested        in dissolution medium without alcohol for all time points.

(5) The formulation in Example 7 was analysed in pH 7.4, USP dissolutionmedium for 12 hours and its corresponding alcoholic medium with 40% v/vof alcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 0.00 4.41 2.00 25.30 25.39 3.00 59.52 49.71 4.00 78.58 68.875.00 91.24 82.92 6.00 95.37 87.91 7.00 97.85 92.02 8.00 99.65 94.91 9.00100.00 97.90 10.00 98.10 11.00 99.17 12.00 100.00

Inference:

-   -   Coated pellets prove to be pH dependent.    -   Values of the release profiles of the coated pellets tested in        40% v/v hydro-alcoholic dissolution medium were resistant when        compared with the release profiles of the coated pellets tested        in dissolution medium without alcohol for all time points.

Example 8 Inventive EUDRAGIT® NE 30D/EUDRAGIT® FS 30D, 7:3/Lubricant:Talc (150% w/w of the Polymer)/138% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 642 192.5 Soluble polymer EUDRAGIT ® FS 30D 275 82.5 Lubricant Talc412.5 412.5 Diluent Water, purified 3254 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio 7:3 using 150% w/w talc as alubricant in coating suspension. The coating was applied in fluid bedprocessor using normal process parameters.

Dissolution Results (Example 8):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

% Drug Release Time in without with 30% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 1.65 0.00 2.00 12.19 6.94 3.00 26.51 15.32 4.00 40.03 23.825.00 53.18 37.18 6.00 63.35 51.35 7.00 73.87 61.19 8.00 79.15 71.20 9.0085.87 78.65 10.00 89.57 83.25 11.00 92.11 86.95 12.00 99.01 90.12

Inference:

Values of the release profiles of the coated pellets tested in 30% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% (v/v) Hr. EtOH EtOH 0.00 0.000.00 1.00 3.36 3.68 2.00 16.63 15.34 3.00 33.61 34.78 4.00 49.98 52.215.00 64.33 69.65 6.00 73.41 79.32 7.00 82.34 87.32 8.00 87.66 96.00 9.0095.45 100.00 10.00 98.29 11.00 100.10 12.00 101.08

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Example 9 Inventive EUDRAGIT® NE 30D/EUDRAGIT® FS 30D, 8:2/Lubricant:Talc (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 733.33 220 Soluble polymer EUDRAGIT ® FS 30D 183.33 55 LubricantTalc 550 550 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio of 8:2 using 200% w/w talc as alubricant. The coating was applied in fluid bed processor using normalprocess parameters.

Dissolution Results (Example 9):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 30% v/v alcohol.

Time % Drug Release in without with 30% (v/v) Hr. EtOH EtOH 0.00 0.000.00 1.00 1.85 0.88 2.00 9.62 5.95 3.00 23.79 13.55 4.00 39.03 22.285.00 52.61 32.57 6.00 65.48 44.26 7.00 74.48 52.18 8.00 82.31 61.38 9.0086.53 67.70 10.00 90.63 74.00 11.00 93.38 80.56 12.00 95.83 84.86

Inference:

Values of the release profiles of the coated pellets tested in 30% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% (v/v) Hr. EtOH EtOH 0.00 0.000.00 1.00 1.85 0.16 2.00 9.62 3.33 3.00 23.79 10.69 4.00 39.03 19.265.00 52.61 29.15 6.00 65.48 41.48 7.00 74.48 52.90 8.00 82.31 61.83 9.0086.53 70.80 10.00 90.63 77.33 11.00 93.38 82.71 12.00 95.83 87.01

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Example 10 Inventive EUDRAGIT® NE 30D/EUDRAGIT® L 30D-55, 9:1/Lubricant:Talc (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 825 247.5 Soluble polymer EUDRAGIT ® L 30D55 92 27.5 Lubricant Talc550 550 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® L30D 55 at a ratio of 9:1 using 200% w/w talc as alubricant. The coating was applied in fluid bed processor using normalprocess parameters.

Dissolution Results (Example 10):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% (v/v) Hr. EtOH EtOH 0.00 0.000.00 1.00 1.26 6.23 2.00 8.56 5.68 3.00 19.06 6.91 4.00 31.19 13.14 5.0042.98 23.92 6.00 51.81 36.42 7.00 58.77 50.15 8.00 68.21 61.71 9.0075.01 71.73 10.00 82.18 79.80 11.00 85.02 86.46 12.00 88.02 91.50

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Example 11 Inventive EUDRAGIT® NE 30D/EUDRAGIT® L 30D-55, 9:1/Lubricant:Talc (125% w/w of the Polymer)/124% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 825 247.5 Soluble polymer EUDRAGIT ® L 30D 55 92 27.5 Lubricant Talc344 344.0 Diluent Water, purified 2865 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® L30D 55 at a ratio of 9:1 using 125% w/w talc as alubricant. The coating was applied in fluid bed processor using normalprocess parameters.

Dissolution Results (Example 11):

Comparative release profiles in phosphate buffered saline pH 6.8, EP andcorresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% (v/v) Hr. EtOH EtOH 0.00 0.000.00 1.00 0.77 7.15 2.00 2.27 14.00 3.00 8.59 23.52 4.00 18.66 33.065.00 28.20 46.05 6.00 39.63 60.64 7.00 52.02 71.79 8.00 60.40 80.41 9.0067.46 86.78 10.00 75.52 89.90 11.00 79.92 95.95 12.00 84.04 96.10

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

Example 12 Inventive EUDRAGIT® NE 30D/EUDRAGIT® FS 30D, 7:3/Lubricant:Titanium Dioxide (200% w/w of the Polymer)/165% w/w Coating/Core

Formulation details of coating suspension for 500 g of cores QuantitySolids Function Ingredients in g in g Insoluble polymer EUDRAGIT ® NE30D 642 192.5 Soluble polymer EUDRAGIT ® FS 30D 275 82.5 LubricantTitanium dioxide 550 550.0 Diluent Water, purified 4033 —

Procedure:

Metoprolol succinate pellets were coated with a mixture of EUDRAGIT® NE30D and EUDRAGIT® FS 30D at a ratio 7:3 using 200% w/w titanium dioxideas a lubricant in coating suspension. The coating was applied in fluidbed processor using normal process parameters.

Dissolution Results (Example 12):

Comparative release profiles in in phosphate buffered saline pH 6.8, EPand corresponding alcoholic medium with 40% v/v alcohol.

% Drug Release Time in without with 40% Hr. EtOH (v/v) EtOH 0.00 0.000.00 1.00 38.53 65.22 2.00 89.71 99.21 3.00 96.38 100.00 4.00 100.00

Inference:

Values of the release profiles of the coated pellets tested in 40% v/vhydro-alcoholic dissolution medium were resistant when compared with therelease profiles of the coated pellets tested in dissolution mediumwithout alcohol for all time points.

1. A pH-dependent controlled release pharmaceutical composition,comprising a core, comprising at least one pharmaceutical activeingredient, with the exception of opioids, wherein the core is coated byat least one coating layer, controlling the release of thepharmaceutical composition, wherein the coating layer comprises apolymer mixture of i) 40-95% by weight, based on dry weight of thepolymer mixture, of at least one water insoluble essentially neutralvinyl polymer or copolymer, and ii) 5-60% by weight, based on dry weightof the polymer mixture, of at least one anionic polymer or copolymer,which is insoluble in a buffered medium below pH 4.0 and soluble atleast in the range from pH 7.0 to pH 8.0, wherein the coating layerfurther comprises 110 to 250% by weight, calculated on dry weight of thepolymer mixture, of a non-porous inert lubricant and the coating layeris present in an amount of at least 60% by weight calculated on theweight of core.
 2. The controlled release pharmaceutical compositionaccording to claim 1 wherein the non-porous inert lubricant is a layeredsilica component, a pigment or a stearate compound.
 3. The controlledrelease pharmaceutical composition according to claim 2 wherein theinert lubricant is talc.
 4. The controlled release pharmaceuticalcomposition according to claim 2 wherein the inert lubricant is Ca- orMg-stearate.
 5. The controlled release pharmaceutical compositionaccording to claim 1, wherein the water insoluble essentially neutralvinyl polymer or copolymer is a copolymer composed of free-radicalpolymerized units of more than 95 up to 100% by weight C₁- to C₄-alkylesters of acrylic or of methacrylic acid and less than 5% by weight ofacrylic or methacrylic acid.
 6. The controlled release pharmaceuticalcomposition according to claim 1, wherein the water insolubleessentially neutral polymer is a polyvinyl acetate type polymer orcopolymer.
 7. The controlled release pharmaceutical compositionaccording to claim 1, wherein the water soluble anionic polymer is a(meth)acrylate copolymer composed of free-radical polymerized units of25 to 95% by weight C₁- to C₄-alkyl esters of acrylic or of methacrylicacid and 5 to 75% by weight (meth)acrylate monomers having an anionicgroup.
 8. A controlled release pharmaceutical composition according toclaim 1, wherein, under in-vitro conditions according to USP paddle, 100rpm, buffered at pH 6.8 in a medium with and without the addition of 40%(v/v) ethanol, when the pharmaceutical active ingredient is released toa degree of less than 20%, the difference in the release rate with theaddition of 40% (v/v) ethanol is not more than plus or minus 15% of thecorresponding release value without 40% (v/v) ethanol, and when thepharmaceutical active ingredient is released to a degree of 20-80%, thedifference in the release rate with the addition of 40% (v/v) ethanol isnot more than plus or minus 30% of the corresponding release valuewithout 40% (v/v) ethanol.
 9. A controlled release pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical activeingredient is metoprolol or an pharmaceutically acceptable salt ofmetoprolol.
 10. A controlled release pharmaceutical compositionaccording to claim 1 in the form of pellets in a multiparticulatepharmaceutical form for instance in the form of a compressed tablet,capsules, sachets, effervescent tablets or reconstitutable powders. 11.A controlled release pharmaceutical composition according to claim 1equipped with a sub coat or a top coat, or both.
 12. A controlledrelease pharmaceutical composition according to claim 1 present in theform of coated pellets or minitablets with an overall average diameterin the range of from 100 to 3000 μm.
 13. A controlled releasepharmaceutical composition according to claim 1 wherein the resultingcoated pellets have an overall average diameter in the range of between100 to 700 μm.
 14. A controlled release pharmaceutical compositionaccording to claim 1 wherein the resulting coated pellets or minitabletshave with an overall average diameter in the range of between 1400 to3000 μm.
 15. A process for preparing a controlled release pharmaceuticalcomposition according to claim 1 comprising: compressing, dry, wet orsintered granules and subsequently rounding said granules off, wet ordry granulating, direct pelleting, powder layering by a processcomprising binding powders onto active ingredient-free beads or neutralcores or active ingredient-containing particles, applying the polymercoating in a spray process, or granulating in a fluidized bed. 16.(canceled)
 17. A method of reducing the release of a pharmaceuticalactive ingredient in the presence of ethanol containing drinkscomprising consuming simultaneously or subsequent to ethanol containingdrinks the controlled release pharmaceutical composition according toclaim 1.